Most recently, it has been found that nanosized cerium oxide (nanoceria) possesses antioxidant activity at physiological pH and has potential use in biomedical applications, such as protection against radiation damage, oxidative stress and inflammation, as reported by various researchers, including R. W. Tarnuzzer, et al. in Nano Lett 2005, 5, 2573; J. P. Chen, et al. in Nature Nanotechnology 2006, 1, 142; J. Niu, et al in Cardiovasc Res 2007, 73, 549; M. Das, et al. in Biomaterials 2007, 28, 1918 and J. M. Perez, et al. in Small 2008.
Biological systems have evolved to utilize readily available elements, such as carbon, oxygen, hydrogen, nitrogen, calcium and iron. Less abundant elements may be utilized as co-factors in enzymatic complex factors, or can be found in chelated forms surrounded by aromatic rings and coordinated bonding. However, many elements, including rare earths, such as cerium, are not present in living organisms, due to their highly reactive nature resulting in toxicity.
Hence, cells do not have protective apparatuses against elements not present in living organisms, and organisms do not have mechanisms to handle the storage, utilization and release of these elements from the body. For instance, lead and arsenic accumulate in the body and can lead to severe pathological conditions, including organ failure and death. Also, nanoparticles composed of metals such as cadmium in Quantum dots (QDOTS) are partially toxic.
Similarly, cerium oxide nanoparticles, despite being potent reactive oxygen species (ROS) scavengers and selective cytoprotective agents, have shown cellular uptake and intracellular residency of cerium oxide nanoparticles which induces dephosphorylation of various substrates, causing aberrant cell signaling and alterations in the transcriptional and post-translational levels, as reported by J. M. Perez et al. in “Synthesis of biocompatible dextran-coated nanoceria with pH-dependent antioxidant properties” Small, 2008. 4(5): 552-556, Tan, F., et al. in “An efficient method for dephosphorylation of phosphopeptides by cerium oxide” J Mass Spectrom, 2008. 43(5): 628-632 and Xia, T., et al. in “Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties” ACS Nano, 2008. 2(10): 2121-2134.
Furthermore, Asati, A., et al. in “Oxidase-Like Activity of Polymer-Coated Cerium Oxide Nanoparticles” Angew Chem Int Ed Engl, 2009 reported the oxidase-like activity of these nanoparticles in acidic microenvironments, which may facilitate the oxidation of intracellular and extracellular components. Most importantly, as cerium is not found in the human body and there are no clearance mechanisms for it, cerium may cause toxicity, contrary to iron oxide nanoparticles, where the iron-containing core can be metabolized and uptaken by ferritin and transferrin, as reported by Xia, T., et al. in “Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties” ACS Nano, 2008, supra and Rzigalinski, B. A., “Nanoparticles and cell longevity” Technol Cancer Res Treat, 2005 4(6): 651-659.
In view of the above findings, potential in vivo application of these nanoparticles has been limited. The prior art in the applications of nanoceria pertains to the administration and use of the nanoparticles free in solution, hence nanoparticle clearance and toxicity may be observed. No prior art reports the encasing of these nanoparticles in a device, such as described in the present invention, thereby preventing direct exposure of the living organism to these nanoparticles.
Thus, a device encapsulating therapeutic elements not present in a living body, such as cerium oxide, is an attractive alternative, preventing the adverse side effects from free nanoparticles in circulation. Therefore, for these reasons, it would be advantageous to introduce nanoparticles within devices to minimize their exposure, accumulation and potential toxicity to biological systems. Such an embodiment would be classified as a prosthetic (implantable) device and not a drug, expediting the adoption of these nanoparticles in therapy and the clinic.
It is desirable to extend the utility of the coated nanoceria particles as a stable, effective, therapeutic device, system or method for detecting reactive oxygen species and monitoring chronic inflammation in biological tissue, while causing no adverse side effects or toxicity to the body. The present invention provides a much needed weapon in the arsenal for treating a broad range of ailments with a pro-inflammatory component, for cancer therapy, for patients with transplants or prosthetic devices and the like.